Myers

Review:

Magnesium-Halogen Exchange

Chem 215

Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Ahn Vu, V. Angew. Chem., Int. Ed. Engl. 2003, 42, 4302. General References on the Preparation and Reactions of Grignard Reagents:

Unlike many lithium-halogen exchange protocols, only one equivalent of i-PrMgX is used in typical experimental procedures. THF is the most common solvent. Ethyl ether has been employed as a solvent for selective exchange of geminal dihalides to generate magnesium carbenoids. The reactivity of Grignard reagents is highly temperature dependant. Only highly reactive electrophiles such as aldehydes and ketones react at significant rates below 0 C. This allows for the preparation of organomagnesium reagents containing cyano, nitro, ester, and imine functional groups, provided that the rate of the exchange reaction is fast enough to allow for exchange at temperatures below 0 C. The rate of magnesium-halogen exchange is accelerated by electron-withdrawing groups on the aromatic ring, and is slowed by electron-donating groups:
I MgBr

Main Group Metals in Organic Synthesis, Yamamoto, H., Oshima, K., Eds.; John Wiley and Sons: New York, 2004. Handbook of Grignard Reagents, Silverman, G. S., Rakita, P. E., Eds.; Marcel Dekker: New York, 1996. Organomagnesium Methods in Organic Synthesis, Wakefield, B. J.; Academic Press: San Diego, 1995.
Development and General Aspects:
RX + R'MgX' RMgX' + R'X

i-PrMgBr
THF, 20 C, 30 min

Analogous to lithium-halogen exchange. The position of the equilibrium varies with the stabilities of the carbanion intermediates involved (sp >> sp2 >> sp3).
Br + EtMgBr Et2O
20 C, 12 h

CO2CH3

CO2CH3

MgBr +

EtBr

Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Ahn Vu, V.; Knochel, P. Synthesis 2002, 565.
I MgBr

Prvost, C. Bull. Soc. Chim. Fr. 1931, 49, 1372. Although the first example was reported in 1931 (above), the preparation of Grignard reagents via metal-halogen exchange has not been widely used until recently. Knochel and coworkers have demonstrated the functional-group tolerance of magnesium-halogen exchange, which is now the method of choice for the preparation of highly functionalized organomagnesium reagents. i-PrMgCl or i-PrMgBr are the most common reagents. In most cases, these reagents can be used interchangeably. i-PrMgBr is made by the Grignard reaction of isopropyl bromide and magnesium turnings. It is less soluble than the chloride (solutions are ~0.8 M), and the titre must be checked more often. i-PrMgCl is commercially available as a 2.0 M solution in THF or diethyl ether. Solutions of i-PrMgX are titrated by the method of Paquette (Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.) According to this procedure, a flame-dried flask is charged with menthol (a non-hygroscopic solid), 1,10-phenanthroline (indicator) and THF. The Grignard reagent is then added until a distinct violet or burgundy color persists.
OCH3

i-PrMgBr
THF, 25 C, 1 h OCH3

Cali, P.; Begtrup, M. Synthesis 2002, 63.

I NO2 PhMgCl THF, 40 C, 30 s NO2 NO2 MgCl NO2

Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610.

Jason Brubaker

 Aryl bromides undergo exchange more slowly than iodides, but electron-poor aryl bromides can still react at temperatures below 0 C.
I MgBr

Dibromides undergo regioselective exchange of the bromine ortho- to a chelating group. Note also the compatibility of the amidine group with the exchange reaction.
N(CH3)2 N N Br NC Br N(CH3)2 CHO MgBr Bu NC Br 68% N N(CH3)2 OH Bu

i-PrMgBr
40 C, 30 min Br Br

i-PrMgBr
THF, 10 C, 1.5 h

NC Br

Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701.
Br F F F Br F F F Br F F F F MgBr F F F MgBr F

Varchi, G.; Jensen, a. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477. Higher temperatures are required for the selective exchange with less effective chelators.
F OCH3 Br F OCH3 MgBr OCH3 CO2H

i-PrMgBr
78 C, 30 min

i-PrMgCl
THF, 40 C, 5 h

CO2

i-PrMgBr
10 C, 1 h F F MgBr

Br

Br

Br 90%

Nishiyama, H.; Isaka, K.; Itoh, K.; Ohno, K.; Nagase, H.; Matsumoto, K.; Yoshiwara, H. J. Org. Chem. 1992, 57, 407.
F

i-PrMgBr
23 C, 2 h F

Functional Groups Compatible with the Magnesium-Halogen Exchange: Ester, benzylic chloride:

Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449.

CO2CH3 Cl

CO2CH3

i-PrMgBr
THF, 30 C, 1 h

CO2CH3 PhN C O 10 C 23 C 75% NPh O

Cl MgBr

Ortho- Directing Groups:

The presence of an chelating ortho- group facilitates exchange; increases the rate of reaction, and allows for low-temperature exchange.
Et O O NC Br CuCN 2LiCl NC 80% OCH2OEt EtO2C

Delacroix, T.; Berillon, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000, 65, 8108. Secondary alkyl tosylate:
OTs O I CH3

Br OCH2OEt NC

BrMg

i-PrMgBr
THF, 30 C, 2 h

i-PrMgCl
THF, 20 C, 1 h

CuCN2LiCl 20 25 C EtO2C 83%

CH3

Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Ahn Vu, V. Angew . Chem., Int. Ed. Engl. 2003, 42, 4302.

Kneisel, F. F.; Monguchi, Y.; Knapp, K. M.; Zipse, H.; Knochel, P. Tetrahedron 2002, 43, 4875. Jason Brubaker

 Nitrile:
OH NC I

Unprotected anilines:
i-PrMgBr
THF, 40 C, 30 min 89% CN NC MgBr PhCHO NC NH2 I I 1. PhMgCl 30 C, 5 min 2. i-PrMgCl 25 C, 10 min CN CN 71% NHMgCl MgCl CHO Bu I NH2 OH Bu

Ph

Tertiary amide:
O N I O N

Varchi, G.; Kofink, C.; Lindsay, D. M.; Ricci, A.; Seconi, G.; Knochel, P. Chem. Commun. 2003, 396.
i-PrMgBr
THF, 25 C, 30 min 81% Br

In the above example, phenyl magnesium chloride is first added because it is a strong base and as a magnesium-halogen exchange reagent it is less reactive than i-PrMgX. This allows for quantitative deprotonation before exchange. Heteroaromatics:

Bomond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701. Heterocycle Amidine, note also the selective exchange of a diiodide:
N(CH3)2 N I I N N(CH3)2 N(CH3)2 1. CuCN2LiCl 2. CO2Et I CH3 O CO2Et 87% Br Br N CH3 I MgBr OEt N I CH3 O F F N S Br N Br F F

Conditionsa (C, h)

Electrophile

Product

Yield (%)

40, 0.5

CO2Et Br (CuCN added)

F F S N

F F OH

80

i-PrMgBr
20 C, 5 min

MgBr

25, 1.5

PhCHO N Br Ph CO2Et N CH3 OH N Bn Ph OEt

75

CO2Et

Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.; Knochel, P. Synlett 2001, 477.
N

20, 1 NC

O N OEt

59

Imine:

i-PrMgBr
THF, 25 C N iPr N iPr

1. BiCl3 2. SiO2 Bi

O Br H 34% Br
a

N Bn

Br

5, 1

PhCHO

Br

73

Murafuji, T.; Nishio, K.; Nagasue, M.; Tanabe, A.; Aono, M.; Sugihara, Y. Synthesis 2000, 1208. Imines can be used to mask aryl aldehydes during the magnesium halogen exchange. The low yield of the reaction sequence above is likely attributable to the second step of the procedure.

CO2Et

30, 1

Br (CuCN added) O CO2Et

80

i-PrMgBr (1.2 equiv), THF

Abarbi, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449.

Jason Brubaker

 Nitro arenes:
NO2 I FG PhMgCl 40 C, 5 min FG NO2 MgCl E+ FG NO2 E

Nitro-substituted organometallic reagents are difficult to prepare through classical methods. These electron-deficient arenes tend to undergo electron-transfer reactions, and direct oxidative addition with elemental magnesium or zinc often leads to reduction of the nitro group. This new procedure is the best method to date for the preparation of nitroarene organometallics. The nitro group must be ortho to the iodide exchanged. Meta- and para-nitro substituted aryl iodides give complex mixtures. PhMgCl is necessary for a successful reaction. More reactive Grignard reagents such as i-PrMgCl give complex mixtures.

Nitro arene
NO2 I

Electrophile

Product
NO2 OH

Yield (%)

PhCHO

Ph

87

For successful reactions with reactive electrophiles such as allyl bromides and acid halides, transmetallation of the organomagnesium intermediate with CuCN2LiCl is necessary.
NO2 I PhCHO Ph 94 NO2 OH

Pd-catalyzed Negishi cross-coupling reactions are possible after transmetallation with ZnBr2:
O NO2 I NC
1. mesitylMgBr, 40 C, 5 min 2. ZnBr2, 40 C, 5 min

CN NO2 I PhCHO CH3O NO2 I cHexCHO EtO2C NO2 I PhCOBr EtO2C NO2 I PhCHO O2N NO2 I I CO2Et Br O2N O2N EtO2C EtO2C CH3O

NO2

CO2Et

1=

CN NO2 OH Ph 72

P 3 CO2Et

3. Pd(dba)2 (5 mol %) 1 (10 mol %), 2 (1.5 equiv) NC 40 23 C, 3 h

2= 73% I

NO2 OH cHex 64

In the case above, mesityl magnesium bromide is used to prevent competing oxidative addition of the aryl iodide generated in the magnesium-iodide exchange reaction.

Magnesium-Halogen Exchange of Vinyl Iodides:

NO2 O
I 1. i-PrMgBr, THF 25 C, 18 h

Ph

Ph

76

2. PhCHO

60% Ph I 1. i-PrMgBr, THF 70 C, 12 h 2. PhCHO CH3O Ph OH 95% Ph

OH

NO2 OH Ph 81

CH3O

NO2

Rottlander, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem. 1999, 64, 1080.
CO2Et 74

Vinyl Iodides are also suitable substrates for magnesium-halogen exchange. Higher temperatures and longer reactions times are required, which limits the functionalgroup tolerance of this method. When the vinyl iodide is substituted with electron-withdrawing groups or chelating heteratoms, the rate of exchange is enhanced. Jason Brubaker

Sapountzis, Ioannis; Knochel, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 1610.

Alternative, More Reactive Reagent Combinations for Magnesium-Halogen Exchange: Lithium Trialkyl Magesium Ate Complexes:

Enhanced Reactivity by Addition of Lithium Chloride to i-PrMgCl prior to exchange (1 equiv):

OH Br 1. i-PrMgClLiCl THF, 0 C, 2 h 2. PhCHO NC 81% Ph

I CH3O

1. Bu3MgLi (1.2 equiv) THF, 78 C, 0.5 h 2. C6H13CHO CH3O 94%

OH C6H13

NC

Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2004, 43, 3333.

Br CH3O

1. Bu3MgLi (1.2 equiv) THF, 0 C, 0.5 h 2. Br CH3O 84%

C6H13

1. i-PrMgClLiCl THF, 40 C, 7 h I 2. DMF

C6H13 H 71%

I Br 1. i-PrBu2MgLi (1.2 equiv) THF, 78 C, 1 h 2. O Br CuCN2LiCl I

1. i-PrMgClLiCl THF, 40 C, 7 h 2. EtCHO

I OH Et 84%

t-BuO

t-BuO
O 66%

Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215. Addition of LiCl to the Grignard reagent produces a more active magnesium-halogen exchange reagent

C10H21

1. i-PrBu2MgLi (1.2 equiv) THF, 0 C, 1 h 2. TMSCl

C10H21 93%

TMS

It has been proposed that LiCl breaks up aggregates of organomagnesium reagents. This more active reagent combination is successful in the exchange of the ortho-phenoxy aryl iodide shown below:

Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333. The lithium trialkyl magnesiates are prepared in situ by the addition of an alkyl lithium (2 equiv) to an alkyl magnesium halide (1 equiv). Magnesiates exhibit a reactivity somewhere between alkyllithium and alkylmagnesium reagents. The exchange reaction is faster and less sensitive to electronic effects (arene substitution). In accord with their greater reactivity, aryl magnesiates show less funtional group tolerance.

CO2Et

1. CH3MgCl, LiCl THF, 30 C, 0.5 h 2. i-PrMgCl 30 C, 0.5 h 3. PhCHO

CO2Et Ph OH OH 62%

I OH

Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004, 2288.

Jason Brubaker